Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major contributor to morbidity and mortality in the US. We propose here a 4-year continuation of our unique and informative Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective study within the ARIC and CHS cohorts. We have several important findings from the previous project period, the three most important being (1) identification for the first time in a prospective study that plasma fibrin fragment D-dimer, a marker of fibrin turnover, is positively and strongly associated with risk of future VTE, (2) verification, again for the first time prospectively, that factor VIII and von Willebrand factor are strong risk factors for VTE, and (3) demonstration that obesity and diabetes are important VTE risk factors, but that most other arterial disease risk factors, including fibrinogen and C-reactive protein, are not. We plan to build upon these findings during LITE continuation, by adding new cases and testing new hypotheses. Our aims are 1. To extend VTE event follow-up in the LITE Study for 4 more years, which is expected to increase the current number of VTE events (n=335) by 47 percent (to n=493), and to sample 1 control per case. In the new cases and controls, we will measure analytes found to be important in LITE already (factor V Leiden, prothrombin G20210A variant, D-dimer, and TAFI), to serve as covariates in combined analyses. 2. To conduct nested case-control studies in the entire sample of 493 VTE cases and 828 controls, using prediagnosis blood and DNA specimens, to determine the prospective associations of VTE with several novel plasma hemostatic factors and genetic markers. 3. To conduct longitudinal analyses of VTE incidence and potential risk factors (or interaction) that we have not yet fully explored: diet, frailty, hormone replacement therapy, and obesity interactions. 4. To study serial blood levels of D-dimer and homocysteine, to better understand their associations with VTE occurrence. Continuation of this comprehensive prospective study will provide additional important epidemiologic insights into the etiology of VTE. This could lead to new strategies for prevention or treatment of VTE.